Platelets Race/ethnicity is an important factor in determining the outcome of coronary heart disease (CHD). Compared to patients of white race/ethnicity, blacks have a 2-fold higher incidence of CHD, and black race/ethnicity is an independent predictor of worse survival after CHD events even when confounding demographic, socioeconomic, and clinical factors are considered (Berry et al., N. Eng. J. Med. 2012, 366, 321-329; Thomas et al., Am. Heart J. 2010, 160, 744-751). Acute coronary events like myocardial infarction (MI) occur when an occlusive platelet thrombus forms at the site of a ruptured atherosclerotic plaque.
P2Y12 and thromboxane receptor inhibition with aspirin and thienopyridines are mainstays of anti-platelet therapy for arterial vascular disease. More recently, the protease-activated receptor (PAR) 1 inhibitor, vorapaxar, was approved for the secondary treatment of patients with prior MI and peripheral vascular disease. Although PAR4 inhibitors have been developed, none have been studied in humans. Thrombin signals through platelet PAR1 and PAR4. These receptors couple to Gq proteins leading to activation of phospholipase Cy, hydrolysis of phosphoinositides and increased cytoplasmic calcium, resulting in activation of integrin αIIbβ3 and platelet aggregation. There are cellular phenotypic differences between PAR1 and PAR4. PAR1 has a higher affinity for thrombin, and Ca2+ transients rise sharply after PAR1 activation with PAR1-activating peptide (PAR1-AP) followed by a fast return to baseline levels. PAR4 stimulation with PAR4-activating peptide (PAR4-AP) induces a more gradual but sustained rise in [Ca2+], which accounts for the majority of intracellular calcium flux. PAR1 blockade with vorapaxar leaves PAR4 as the only means by which thrombin can activate platelets. PAR4 inhibition has a potential therapeutic advantage of inhibiting the maximal thrombin effect while minimizing bleeding because PAR1 signaling remains intact.